New oxido-steroids and process for their manufacture



United States Patent 3 178,346 NEW oxrno-srnnbms AND raocnss Foa THEIRMANUFACTURE Albert Wettstein, Julius Schmidlin, Karl Heusler, and PeterWieland, Basel, Switzerland, assignors to Ciba Corporation, acorporation of Delaware No Drawing. Filed Oct. 8, 1959, Ser. No. 845,095

Claims priority, application Switzerland, Oct. it), 1958,v

15 Claims. c1. 167-65) The present invention provides new saturated andunsaturated 11218-oxygenated steroids of the partial general formulaCHzRg O-CH2 a F ,QU

in which R represents a hydrogen atom or a free hydroxyl group, and Rrepresents a hydrogen atom or a free, esterified 'or etherified hydroxylgroup, and also androstenes of the formula in which R represents ahydrogen atom together with a free, esterified, or etherified hydroxylgroup or an alkyl group together with a free hydroxyl group, or an oxogroup. The new compounds are also useful as intermediate products forthe manufacture of medicaments. Thus they may be oxidised with the aidof chromium trioxide or ruthenium tetroxide to obtain the corresponding(11 18)-lactones, which are either physiologically active themselves orrepresent intermediates, e.g., for the synthesis of aldosterone typecompounds.

The new llflzlS-oxido-steroids are obtained by treating a saturated orunsaturated llflzl8-dihydroxy-steroid or an O-monoacyl-derivativethereof, especially an 18- O-acyl derivative thereof, with an agentcapable of splitting off water or acid, and, if desired, esterifying anyhydroxyl group present in the resulting 115:18-oxido-steroid and/orhydrolyzing any acetaliz ed oxo group. The said 11,6:18-oxido-steroidscan be obtained by the process of this invention in a very simple andunexpected manlCC nor by treating an 11,8:18-dihydroXy-steroid with anacid, for example, a lower aliphatic carboxylic acid, such as aceticacid or propionic acid, advantageously in the presence of water. Afurther advantageous form of the process consists in splitting ofi acidfrom an O-monoacyl-derivative, especially an 18-O-acyl derivative, of an15:18-dihydroxy-steroid by means of a base, for example, an alkali saltof carbonic acid, such as an alkali hydrogen carbonate, in an aqueousalcohol, for example, aqueous methanol. The initial esterification andSplitting off of acid in accordance with the process can be carried outwith advantage in a single operation, for example, by the action of ahalide of an acid of phosphorus or of sulfuric acid or by the action ofa sulfonic acid halide, for example, paratoluene sulfochloride ormethane sulfochloride, and a tertiary amine, such as pyridine,collidine, etc.

The products of the process are saturated or unsaturated, racemic oroptically active 11:18-oxido-steroids, among which there are hereinafterincluded also l9-nor and D-horno-steroids. There may be mentioned, moreespecially, 4- or S-unsaturated 11:18-oxides of the pregnane serieshaving oxygen substituents at positions 3 and 20 or 3, 20 and 21 or3,17, 20 and 21, or containing radicals convertible into suchsubstituents, and also 4- or S-unsaturated 11:18-oxido-compounds of theandrostane series having oxygen substituents in the 3- and 17- positionor radicals convertible-into such substituents. The aforesaid11:18-oxido-steroids may possess any desired configuration and, inaddition to any further double bonds present, for example, in the 1-,6-, 7-, 14- or 16-positions, may be further substituted, for example,

by free or functionally converted hydroxyl groups, oxo

groups or halogen atoms. If desired, hydroxyl groups present in theresulting 11:18-oxido-steroids may be esterified by a method in itselfknown by reaction with a reactive derivative of a saturated orunsaturated aliphatic, cycloaliphatic, aromatic or heterocycliccarboxylic acid, preferably of lower aliphatic, monocycliccycloaliphatic, aromatic or heterocyclic carboxylic acid, lowermonocyclic araliphatic or cycloaliphatic carboxylic acid, for example,with such derivative of formic acid, acetic acid, chloracetic acid,trifluoroacetic acid, carbamic acids, alkoxy-carboxylic acids, propionicacid, butyric acids, lactic acid, valeric acids such as n-valeric acidor trimethyl-acetic acid, diethyl-acetic acid, caproic acids such asfi-trirnethyl-propionic acid, oenanthic, caprylic, pelargonic, capric orundecylic acids, for example, undecylenic acid, lauric, myristic,palmitic or stearic acids, for example, oleic acid, or crotonic acid,undecane acid, cyclopentyl-, cyclohexylor phenyl-acetic acidsor,-propionio acids, hexahydrobenzoic acid, benzoic acid, phenoxyalkaneacids such as phenoxy-aceticacid, para-chloro-phenoxy-acetic acid,2:4-dichlorophenoxy-acetic acid, 4-tertiary-butyl phenoxy-acetic acid,3-phenoxy-propionic acid, 4-phenoxy-butyric acid, furane-Z-carboxylicacid, S-tertiary-butyl-furane-Z-carboxylic acid, S-bromo-furane-Z-carboxylic acid, nicotinic acid, or isonicotinic acid, and

- also dicarboxylic acids, such as oxalic acid, succinic acid,

maleic acid, glutaric acid, dimethyl-glutaric acid, pimelic acid,acetone-dicarboxylic acid, phthalic acid, tetrahydrophthalic acid,hexahydrophthalic acid, endomethylene-tetrahydrophthalic acid,endomethylene-hexahydrophthalic acid, endoxy-hexahydrophthalic acid,endoxytetrahydrophthalic acid, camphoric acid, cyclopropane dicarboxylicacid, cyclobutanedicarboxylic acid, diglycollic acid,ethylene-bis-glycollic acid, polyethylene-bis-glycollic acids,quinolinic acid, cinchomeronic acid, and also the polyethylene glycolmonoalkyl ether semi-esters of the aforesaid dicarboxylic acids, orketo-carboxylic acids such as ,B-keto-carboxylic acids, for example,acetoacetic acid, propionyl-acetic acid, butyryl-acetic acid,caprionoyl-acetic acid, amino-acids such as diethylamino-acetic acidetc. Instead of carboxylic acids there may be used sulfonic acids, suchas methane sulfonic acid or toluene sulfonic acid, and also inorganicacids, such as phosphoric or sulfuric acids.

The 11,8:18-dihydroxy-steroids used as starting materials or their18-O-acyl-derivatives are more especially those of the pregnane andandrostane series. They can be made by methods in themselves known fromthe appropriate (18 1l)-lactones or from llfl-hydroxy-lS-aldehydes ortheir 11:18-semi-acetals or 11:18-semi-acetalacylates by reduction withcomplex metal hydrides, such as lithium-aluminum hydride, aluminumborohydride and sodium borohydride. In this method of preparation anyoxo groups present are, if desired, first protected by acetalization orketalization. During the conversion into the new llfizl8-oxido-steroidswith acids, in this case, the protective groups can be removedsimultaneously, so that the free final products are obtained in anespecially simple manner in a single process step.

Apart from the free 115:l8-dihydroxy-compounds, there may be used asstarting materials in the process described above, theirO-monoacyl-derivatives, especially their IS-O-acyI-derivatives. They areobtainable from the 115:18-diols in known manner by reaction withreactive derivatives of saturated or unsaturated aliphatic orcycloaliphatic, araliphatic, aromatic or heterocyclic carboxylic acids,and especially the carboxylic acid halides or anhydrides. The reactionis carried out in the presence of an acid-binding agent, for example, atertiary base, such as pyridine, dimethylaniline or collidine, or a saltof the acid in question.

The invention also includes compositions for use in human or veterinarymedicine, which contain the aforesaid llflzlS-oxido-steroids and a solidor liquid carrier for medicaments. These compositions can be prepared bymethods in themselves known, for example, with the use of pharmaceuticalorganic or inorganic carriers suitable for parenteral, enteral ortopical administration. As carriers there are used substances that donot react with the products of this invention, for example, water,vegetable oils, benzyl alcohols, polyethylene glycols, gelatine,lactose, starches, magnesium stearates, talc, White petroleum jelly,cholesterol or other carriers for medicaments. Especially suitable arepreparations for parenteral administration, advantageously solutions,and preferably oily or aqueous solutions, and also suspensions,emulsions, implantation preparations. For enteral administration thereare likewise used tablets or dragees, and for topical administrationsalves or creams may be used. If desired, the preparations may besterilised or may contain auxiliary substances, such as preserving,stabilising, wetting, or emulsifying agents, salts for regulating theosmotic pressure or buffers. The content of active substance in thesepreparations, such as an ampoule or a tablet is within the range of0.1-200 milligrams, or 0.03-60%.

The following examples illustrate the invention:

Example 1 A solution of 366 mg. of the partially acetylated d,l A3:3;20z20 bis ethylenedioxy 11 3:1821 trihydroxy-pregnene describedbelow in 7.5 cc. of acetic acid of 90% strength is boiled under refluxfor one hour in an atmosphere of nitrogen. The mixture is then cooled,the greater part of the acetic acid is evaporated in vacuo while addinga total of 15 cc. of water, and the suspension, which has beenconcentrated to a volume of 2.5 cc., is extracted with methylenechloride. The extracts are washed with an 0.5 N-solution of sodiumhydrogen carbonate and water, then dried with sodium sulfate andevaporated after being combined. There is obtained a crystalline crudeproduct, which is split up by chromatography in the systemformamide/cyclohexane-benzene (1:2) after application to 100 sheets ofWhatman paper No. 1 (18.5 x 45 cm.). After drying the paper at 40 C. ina high vacuum, the two main zones having Rf-values of 0.10-0.16 and 0.58to 0.66, which strongly reduce blue tetrazolium salt and absorb in theultra-violet spectrum, are eluted with aqueous tetrahydrofurane of 20%strength and of 40% strength, the collected extracts are concentrated invacuo to about of their original volumes, and the two concentrates areextracted with methylene chloride. The extracts are washed with a smallquantity of water; dried with sodium sulfate, and are evaporated,whereby 93 mg. of a crystalline residue from the lower zone and mg. of acrystalline residue from the upper zone remain behind.

The crude eluate from the lower zone is dissolved in 3 cc. of benzene,the solution is filtered through a column of 250 mg. of active carbonfollowed by washing the column with benzene, and the colorless filtrateis evaporated in vacuo. From the residue there are obtained byrecrystallisation from a mixture of methylene chloride and ether 66 mg.of d:l-A -3:20-dioxo-11B:18-oxido-21-acet0xypregnene melting at 132-134C./152-154 C. (dimorphism).

The crude eluate from the upper zone is dissolved in 3 cc. oftetrahydrofurane and purified over 80 mg. of active carbon in ananalogous manner. From the acetone-ether solution there are obtained 58mg. of dzl-A -3z20-dioxo- 11/3:18-oxido-2l-hydroxy-pregnene melting at168-170" C. By subjecting the latter to the action of an excess ofacetic anhydride and pyridine for 14 /2 hours at room temperature, theketol is substantially quantitatively converted into the acetate meltingat 132-134 C./152-154 C. isolated from the lower zone.

The starting material used in this example may be prepared as follows:

1.116 grams of the (18- 11)-lactone of d:l-A -3:3;20:20-bis-ethylenedioxy-1 113 21-dihydroxy-pregnene-18 acid are coveredwith 37.5 cc. of anhydrous tetrahydrofurane and 25.3 cc. of a 1.0-molarsolution of lithium alanate in tetrahydrofurane, and the mixture isstirred for 122 hours at room temperature in an atmosphere of nitrogen.The reaction mixture is diluted with 137.5 cc. of anhydroustetrahydrofurane and cooled to 0-3 C., and there is added in the courseof one hour an anhydrous mixture of 6.25 cc. of ethyl acetate and 18.75cc. of tetrahydrofurane, then a mixture of 2.3 cc. of water and 23 cc.of tetrahydrofurane is added in the course of a further hour, andfinally 1.0 gram of purified kieselguhr is added. After a further 30minutes stirring at 0-3 C., the suspension is filtered with suctionthrough a thin layer of kieselguhr, followed by washing with 225 cc. oftetrahydrofurane, and the filtrate is evaporated in vacuo. Thecrystalline residue obtained from ether is crude dzl-A -33;20:20-bis-ethylenedioxy-llfl:18:ZI-trihydroxy-pregnene, which can thenbe used directly in the acetylation described below. The product can beobtained in a very pure form by adsorption chromatography over 50 timesits Weight of silica gel. It is dissolved from this adsorbent with ethylacetate, and crystallises from ether in small clusters melting at 118-120 C./148150 C. (dimorphism).

A solution of 369 mg. of crude d:l-A-3:3;20:20-bisethylene-dioxy-ll/i:18:21-trihydroxy-pregnene in 14.5 cc.of a l-molar mixture each of acetic anhydride and pyridine in anhydroustetrahydrofurane is allowed to stand with the exclusion of moisture for21 hours at room temperature, then the reaction solution is evaporatedfirst under the reduced pressure of a waterjet pump and then under ahigh vacuum pump while a total of 27.5 cc. of toluene is added, and theresidue is taken up in ether. By repeatedly applying ether andevaporating, there are finally obtained 366 mg. of an almost completelycrystalline acetylation product, which is used directly for thetreatment with acetic acid of strength described above.

Example 2 A solution of 204 mg. of d:l-A-3:3;20:20-bis-ethylenedioxy-llp:18-dihydroxy-pregnene in 4 cc. ofacetic acid of 50% strength is heated for 15 minutes on a boiling Waterbath in an atmosphere of nitrogen. After cooling the mixture to roomtemperature, the greater part of the acetic acid is distilled off whileadding a total of 4.5 cc. of water, and the aqueous residue is extractedwith methylene chloride. The methylene chloride extracts are washed withan 0.5 N-solution of sodium-hydrogen carbonate and Water, dried withsodium sulfate and evaporated. The crude product is transferred to 80sheets of Whatman paper No. 1 (18.5 x 45 cm.) for purification and ischromatographed down to the edge in the systemformamide/cycloheXane-benzene (1: 1). From the strongly ultra-violetabsorbing zone having an Rf-value of 0.60- 0.73 there are obtained','byelution with aqueous tetrahydrofurane of 20% strength and of 40%strength, distilling olf the tetrahydrofurane and extractively workingup the concentrate with methylene chloride, 140.4 mg. of a productwhich, after recrystallisation from ether, yields 114 mg. of puredzl-M-3z20-dioxo-11fl:18-0xido-pregnene melting at 162 C./17818l.5 C.(dimorphism).

The starting material used in this example is prepared as follows:

To a solution of 808 mg. of the (18 11)-lactone of d l-A -3 3 ;20:20-bis-ethylenedioxy-1 1 fl-hydroxy-pregnene- 18 acid in 33 cc. ofanhydrous tetrahydrofurane are added in the course of 15 minutes, Whilestirring, 4.=l cc. of an 0.460molar solution of lithium-aluminum hydridein tetrahydrofurane. When the mixture has been stirred for a further 3%hours at room temperature, the opalescent solution is poured, followedby rinsing out with 8.1 cc. of tetrahydrofurane, on to a mixture of 18.8cc. of a l-molar solution of potassium sodium tartrate, 7.5 cc. of 0.5molar tartaric acid and 26.5 grams of ice, and the whole is concentratedin vacuo to a final volume of 15 cc. The aqueous suspension is thenextracted with methylene chloride, the extract is washed with a l-molarsolution of potassium sodium tartrate and with water, and dried Withsodium sulfate and evaporated. The residue crystallises almostcompletely from ether, and is crude d:l-A -3:3;20:20-bis-ethylenedioxy1113:18 dihydroxypregnene melting at ISO-155 C. The productissufiiciently pure for the treatment with acetic acid of 50% strengthdescribed above.

A solution of 88 mg. of d:l-A -3:3;20:20-bis-ethylenedioxy-llfizl8-dihydroxy-pregnene in 2.0 cc. of benzene and 0.085 cc. of anhydrouspyridine, which solution has been prepared with the exclusion ofmoisture in. an atmosphere of nitrogen, is mixed dropwise in the courseof 15 minutes with 0.70 cc. of trifluoracetic anhydride, while coolingWith ice. When the dropwise addition is complete, the cooling bath isremoved and the whole is stirred for a further five. hours at roomtemperature. The reaction mixture is then poured onto a mixture of 5 cc.of a2 N- solution of sodium carbonate and 7.5 grams of ice, and isextracted with benzene. The benzene extracts are washed with 0.5 Nphosphoric acid, a 2 N-solution of sodium carbonate and with Water, thecombined extracts are dried with sodium sulfate and evaporated. From thebenzene-free residue there are obtained by recrystallisation from amixture of ether and petroleum ether (1: l) 84 mg. of pure dzl-A-3z3;20:20-bis-ethylenedioxy-11,8:18- bis-trifluoracetoxy-pregnenemelting at 196.5-199 C. with slight decomposition.

Example.3

To a solution of 3.9 mg. of d:l-A-3:2O-dioxo-1LB-hydroxy-18-acetoxy-pregnene in 0.5 cc. of methanol isadded 0.10 cc. of an 0.5-molar solution of potassium hydrogen carbonate,and the mixture is allowed to stand at room temperature for 96 hours inan atmosphere of nitrogen. At the end of this period the reactionsolution is freed tion of water, and the aqueous residue is extractedwith methylene chloride. The extract solution is Washed with water,dried with sodium sulfate and evaporated. The

residue is chromatographed down' to the edge in the systemformamide/cyclohexane-benzene (1:1) on four sheets of Whatman paper No.1 (18.5 x 45 cm.). The

zone which absorbs ultra-violet light and has an Rf-value of 0.70.8 isdried for 16 hours in a high vacuum, the paper is then eluted withaqueous tetrahydrofurane of 20% strength, the combined extract solutionsare concentrated in vacuo to of their original volume, and theconcentrate is extracted with methylene chloride. The methylene chlorideextracts are washed with water, dried and evaporated. The residue (2.6mg.) yields, after recrystallisation from a mixture of methylenechloride and ether, d:l-A -3:2.0 dioxo-11/3-18-0xido-pregnene melting at162 C./l78181.5 C. (dimorphism).

The starting material used in this example can be prepared from thed:l-A -3:3;20:ZO-bis-ethylenedioxy- :18-dihydroxy-preguene described inExample 2 in the following manner: 7

A solution of 612 mg. of crude d:l-A-3:3;20:20-bisethylenedioxy-llfi:l8-dihydroxy-pregnene in 5.75 cc. ofanhydrous pyridine is mixed with 3.35 cc. of acetic anhydride, and themixture is heated for 2 hours with the exclusion of moisture in a bathhaving a temperature of 65 C. The reaction solution is then evaporatedunder a high vacuum pump, the residue is dissolved in a small amount ofether, and, after evaporation, there are obtained 680 mg. of crudecrystalline d:l-A -3:3;20:20-bisethylenedioxy-l 1 ,B-hydroxy-lS-acetoxy-pregnene.

680 mg. of the latter compound are covered with 17 cc. of acetic acid of67% strength, and the mixture is heated for 30 minutes on a boilingwater bath in an atmosphere of nitrogen, while stirring. After beingcooled, the reaction mixture is concentrated to about 3 cc. with theaddition of a total of 20 cc. of water, the aqueous residue is extractedwith methylene chloride, the extract is washedwith an 0.5 N-solution ofsodium hydrogen carbonate and with water,then dried with sodium sulfateand evaporated. There are obtained 524 mg. of a crude product, which issplit up by chromatography in the system formamide/cyclohexane-benzene(1:2), after being applied to sheets of Whatman paper No. 1 (18.5 x 45cm.). The chromatogram which extends down to the edge exhibits threezones that absorb ultraviolet light strongly. The uppermost zone havingan Rf-value of 0.12-0.23 is cut out, dried in a high vacuum for 16hours, and then eluted with aqueous tetrahydrofurane of 20% strength andof 50% strength. The combined extracts are concentrated in vacuo toabout of their original volume, and the concentrate is then extractedwith benzene. The extracts are washed with a small amount of water,dried with sodium sulfate, and evaporated. There are obtained 189 mg. ofa crystalline eluate and there are obtained therefrom byrecrystallisation from a mixture of methylene chloride and ether 166 mg.of pure d:l-A. -3 ZO-dioxo-l 1 fl-hydroxy-l S-acetoxy-pregnene meltingat 190.5-192.5 C.

Example 4 A collected fraction of crude d:l-A -3:3-ethylenedioxy-115:175 dihydroxy-l8-acetoxy-androstene, obtained in the mannerdescribed below from 720 mg. of d:l-A -3:3- ethylenedioxy 11,8hydroxy-17-oxo-18-acetoxy-androstene by reduction with sodiumborohydride followed by chromatographic separation on silica gel, istreated in boiling acetone with 20 mg. of Carboraffin then filtered toremove the active carbon and evaporated in vacuo. The residue isdissolved in a small amount of methylene chloride, and by allowing thesolution to stand with the addition of ether 35 mg. of the reductionproduct used separate out. The remainder is taken up in 10 cc. ofbenzene, and chromatographed on 30 grams of silica gel containing 15% ofwater. From the fractions dissolved out with a mixture of benzene andethylacetate (9:1) there is obtained, after recrystallisation from amixture of acetone 7 and ether, pure d:l-A-3:3-ethylenedioxy-1l/3:18-oxido- 17/3-acetoxy-androstene melting at213.5-218.5 C.

A solution of 38 mg. of dzl-A -3:3-ethylenedioxy-11B:18-oxido-17/3-acetoxy-androstene in 1.1 cc. of acetic acid of 90%strength is heated for minutes at 100 C. The reaction mixture is cooledand evaporated under a high vacuum with repeated additions of benzene,and the residual -oil is dissolved in a small amount of ether. Uponstanding colorless crystals of d:l-A -3-oxo-11B:18-oxido-17fl-acetoxy-androstene melting at 162164.5 C. separate out.

The starting material used in this example may be prepared as follows:

A solution of 31 mg. of sodium borohydride in 0.5 cc. of water and 10cc. of tetrahydrofurane is added, while stirring to a solution of 800mg. of d:l-A -3:3-ethylenedioxy-lLB-hydroxy-l7-oxo-18-acetoxy-androstenein 40 cc. of anhydrous tetrahydrofurane. After six hours a further 5 mg.of sodium borohydride are added, and the whole is stirred for a further16 hours at room temperature. The excess of reducing agent is thendecomposed by the addition of 1.1 cc. of acetic acid of 10% strength,the mixture is diluted with 150 cc. of water and 100 cc. of a saturatedsolution of sodium chloride, and extracted with chloroform. The extractsolution is washed with saturated sodium chloride solution and withWater, then dried and evaporated. The residue is dissolved in 10 cc. ofbenzene and chromatographed over 40 grams of silica gel containing ofwater. From the fractions eluted with mixtures of benzene and ethylacetate (9:1) and (17:3) there are obtained by recrystallisation from amixture of methylene chloride and ether 440 mg. of dzl-A 3:3ethylenedioxy 11p:18-dihydroxy-17fi-acetoxy-androstene melting at191.5-193.5 C. The substance (145 mg.) dissolved out with a mixture ofbenzene and ethyl acetate (7:3) yields, on recrystallisation from amixture of methylene chloride and ether, d:l-A-3:3-ethylene-dioxy-11,8:17,8-dihydroxy-18-acetoxy-androstene melting at209.5-212.5 C. with decomposition.

160 mg. of dzl-A -3:3-ethylenedioxy-11B:IS-dihydroxy-17/3-acetoxy-androstene are dissolved in 12 cc. of ethanol of 95%strength and, after the addition of 0.1 gram of platinum oxide,hydrogenated to completion. The solution is filtered to remove thecatalyst, and by evaporating the solution there is obtaineddzl-3:3-ethylenedioxy-11B: 1 S-dihydroxy-17(3-acetoxy-androstane.

Example 5 To a solution of 90 mg. of d:l-A -3:3-ethylenedioxy- 113:1S-dihydroxy-l7fi-acetoxy-androstene in 1 cc. of pyridine are added,while stirring, 50 mg. of para-toluene sulfochloride, and the mixture isallowed to stand for 17 hours at room temperature. The reaction mixtureis then poured onto ice and the aqueous phase is extracted withmethylene chloride. The extract solution is washed with a 1 N-solutionof sodium carbonate and with water, then dried and evaporated. Theresidue yields from a mixture of methylene chloride and ether crystalswhich sublime at 170 C. in a high vacuum. By recrystallising thesublimate from a mixture of methylene chloride and ether, there isobtained dzl-A -3z3-ethylene-dioxy-l 1,8:18-oxido l7fi-actoxy-androstenemelting at 213.5218.5 C., which is identical with the ketal ob- .tainedas described in Example 4.

The starting material used in this example can be prepared according tothe directions given in Example 4. By using as starting material in thisexample the corresponding saturated diol, namelyd:l3:3-ethylenedioxy-llp: 18 dihydroxy 17p acetoxy androstane, the

8 preparation of which is described at the end of Example 4, there isobtained d:l-3:3-ethylenedioxy-11p:18-oxido- 17/3-acetoxy-ar1drostane.

What is claimed is:

1. Process for the manufacture of a member selected from the groupconsisting of llflzl8-oxido-androstanes and :18-oxido-pregnanes, whereinthe corresponding 1118:l 8-dihydroxy-steroid is reacted with a memberselected from the group consisting of an acid, a halide and anhydridethereof and any resulting 18-O-acyl derivative is treated with a base.

2. Process as claimed in claim 1, wherein a tertiary amine is used asbase.

3. Process as claimed in claim 2, wherein pyridine is used as base.

4. Process as claimed in claim 1, wherein the halide of a sulfonic acidis used.

5. Process as claimed in claim 1, wherein para-toluene sulfonyl chlorideis used as the halide of a sulfonic acid.

6. Process as claimed in claim 1, wherein a lower aliphatic carboxylicacid is used as acid.

7. Process as claimed in claim 6, wherein acetic acid is used as acid.

8. Process as claimed in claim 1, wherein an alkali metal salt ofcarbonic acid in an aqueous alcohol is used as base.

9. Process as claimed in claim 8, wherein an alkali hydrogen carbonatein aqueous methanol is used.

10. A compound of the formula in which R represents a member selectedfrom the group consisting of oxo, B-hydroxy and hydrogen, fl-hydroxy andlower alkyl and ,B-acyloxy and hydrogen, the acyloxy radical beingderived from a fatty acid having 2 to 18 carbon atoms.

1 1. 1 1 3: 1g8-oxido-progesterone.

12. 111/3:18 oxido-testosterone acetate.

13. 3:3-ethylenedioxy-11 9:18-dihydroxy-17fl acetoxyandrostane.

14. A pharmaceutical composition comprising the compounds claimed inclaim 10, containing the active ingredient in an amount ranging from0.03-60% together with a suitable pharmaceutical carrier.

15. A pharmaceutical composition comprising the compound claimed inclaim 11, containing the active ingredient in an amount ranging from0.03-60% together with a suitable pharmaceutical carrier.

References Cited by the Examiner UNITED STATES PATENTS 2,904,545 9/59Reichstein et al. 260-23955 2,959,586 11/60 Kerwin et al. 260-239553,040,039 6/62 Wettstein et al. 260239.55

OTHER REFERENCES Heusler et al.: Helvetica Chim. Acta (1958), vol. 41,No. 4, page 1006.

LEWIS GOTTS, Primary Examiner.

L. H. GASTON, Examiner.

10. A COMPOUND OF THE FORMULA
 14. A PHARMACEUTICAL COMPOSITIONCOMPRISING THE COMPOUNDS CLAIMED IN CLAIM 10, CONTAINING THE ACTIVEINGREDIENT IN AN AMOUNT RANGING FROM 0.03-60% TOGETHER WITH A SUITABLEPHARMACEUTICAL CARRIER.